Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
  • C07D491/22—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains four or more hetero rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
  • C07D491/12—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains three hetero rings
  • C07D491/18—Bridged systems

Definitions

• the present invention relates to improved processes for preparing lactam morphinans.
• the processes generally transform keto-morphinans to seven- membered lactam morphinans using a hydroxyamine sulfonic acid reagent.
• Morphinan compounds are important pharmaceuticals showing a variety of activity. Modifications to the core morphinan structure may show increased or varying biological activities. Specifically, modification of the core ring structure is a desirable scaffold for new therapeutics.
• Several ring enlargement reactions are known for expanding small molecules with few functionalities, however, their application to morphinans has had limited success.
• the Schmidt reaction is a ring expansion reaction that utilizes a hydrazoic acid. Rather than expansion of the ring structure in the morphinan compound, the Schmidt reaction results in cleavage of the morphinan ether ring. Beckmann rearrangements have also been attempted in morphinans. Generally, the Beckmann reaction proceeds from an oxime which is then contacted with an acid to give an amide or lactam. Previous attempts to utilize a Beckmann rearrangement on morphinan oximes resulted in poor yields and mixtures of products.
• the present invention relates to a process for producing seven- membered lactam morphinans.
• the present invention provides a process for producing a seven-membered lactam morphinan.
• the process comprises contacting a keto-morphinan with a hydroxyamine sulfonic acid to form the seven-membered lactam morphinan.
• keto-morphinan is a compound comprising Formula (I) and the seven-membered lactam morphinan is a compound comprising Formula (III):
• R 1 , R 2 , R 3 , R 5 , R 7 , R 8 , and R 10 are independently chosen from hydrogen, hydrocarbyl, substituted hydrocarbyl, halogen, and ⁇ - ⁇ OR 15 ;
• R 14 is chosen from hydrogen and ⁇ - ⁇ OR 15 ;
• R 5 is chosen from hydrogen, hydrocarbyl, and substituted hydrocarbyl
• R 17 is chosen from hydrogen, hydrocarbyl, and substituted hydrocarbyl.
• keto-morphinan is a compound comprising Formula (II) and the seven-membered lactam morphinan is a compound comprising Formula (IV):
• R , R 2 , R 3 , R 5 , R 7 , R 8 , and R 10 are independently chosen from hydrogen, hydrocarbyl, substituted hydrocarbyl, halogen, and ⁇ - ⁇ OR 15 ;
• R 14 is chosen from hydrogen and ⁇ - ⁇ OR 15 ;
• R 15 is chosen from hydrogen, hydrocarbyl, and substituted hydrocarbyl
• R 7 is chosen from hydrogen, hydrocarbyl, and substituted hydrocarbyl
• R 18 is chosen from hydrogen, hydrocarbyl, and substituted hydrocarbyl
• X is chosen from fluorine, chlorine, bromine, and iodine.
• the present invention relates to the synthesis of seven-membered lactam morphinans using a hydroxyamine sulfonic acid.
• the process produces seven-membered lactam morphinans in high yields and with few undesired byproducts.
• the reaction proceeds from the keto-morphinan without the isolation of an oxime intermediate, resulting in a more facile transformation of the keto- morphinan to the seven-membered lactam.
• the core morphinan structure generally consists of the fused ring structure shown below.
• the structure below shows the numbering associated with individual atoms of the alkaloid ring structure.
• the processes described herein result in a modification of the core structure.
• the process results in an expansion of a six- membered ring to a seven-membered ring.
• the core structure can be substituted as described herein. These compounds have stereocenters, and thus, each stereocenter may have an R or an S configuration such that both C-15 and C-16 are on the same side of the molecule.
• the processes for producing the seven-membered lactam morphinans comprise contacting a keto-morphinan with a hydroxyamine sulfonic acid.
• the process further comprises a work-up with a proton donor or an organic solvent such that the seven-membered lactam may be isolated from the reaction mixture.
• Keto-morphinans are morphinan compounds having a ketone group. Keto-morphinans may be naturally occurring morphinans or may be synthetically prepared. In preferred embodiments, the keto-morphinan is a 6-keto-morphinan, meaning that the carbon atom of the ketone group is at the 6-position of the core morphinan structure. In some aspects of the invention, the keto-morphinan is a compound comprising Formula (I):
• R 1 , R 2 , R 3 , R 5 , R 7 , R 8 , and R 0 are independently chosen from hydrogen, hydrocarbyl, substituted hydrocarbyl, halogen, and ⁇ - ⁇ OR 15 ;
• R 14 is chosen from hydrogen and ⁇ - ⁇ OR 15 ;
• R 5 is chosen from hydrogen, hydrocarbyl, and substituted hydrocarbyl
• R 7 is chosen from hydrogen, hydrocarbyl, and substituted hydrocarbyl.
• R ⁇ R 2 , R 5 , R 7 , R 8 , and R 10 are hydrogen; R 3 and R 14 are selected from hydrogen, ⁇ - ⁇ OH and ⁇ - ⁇ OCH 3 ; and R 7 is selected from allyl, cyclopropylmethyl, and methyl.
• R 1 , R 2 , R 5 , R 7 R 8 , R 10 and R 4 are hydrogen; R 3 is ⁇ - ⁇ OCH 3 ; and R 17 is methyl.
• R 1 , R 2 , R 5 , R 7 , R 8 , and R 0 are hydrogen; R 3 is hydroxyl; R 14 is hydroxyl; and R 7 is cyclopropylmethyl.
• R 1 , R 2 , R 5 , R 7 , R 8 , and R 10 are hydrogen; R 3 is hydroxyl; R 4 is hydroxyl; and R 7 is methyl.
• R , R 2 , R 5 , R 7 , R 8 , and R 10 are hydrogen; R 3 is hydroxyl; R 14 is hydroxyl; and R 17 is allyl.
• keto-morphinan is a compound comprising Formula (II):
• R 1 , R 2 , R 3 , R 5 , R 7 , R 8 , and R 0 are independently chosen from hydrogen, hydrocarbyf, substituted hydrocarbyl, halogen, and ⁇ - ⁇ OR 15 ;
• R 14 is chosen from hydrogen and ⁇ - ⁇ OR 15 ;
• R 15 is chosen from hydrogen, hydrocarbyl, and substituted hydrocarbyl
• R 17 is chosen from hydrogen, hydrocarbyl, and substituted hydrocarbyl
• R 18 is chosen from hydrogen, hydrocarbyl, and substituted hydrocarbyl
• X is chosen from fluorine, chlorine, bromine, and iodine.
• R 1 , R 2 , R 5 , R 7 , R 8 , and R 10 are hydrogen; R 3 is hydroxyl; R 14 is hydroxyl; R 17 is cyclopropylmethyl; R 8 is methyl; and X is bromine.
• the keto-morphinan may have a particular stereochemical configuration.
• keto-morphinans have at least four stereocenters at C-5, C-9, C-13, and C14.
• the C-5, C-9, C-13, and C-14 carbons of the keto-morphinans may be either R or S, so long as both C-15 and C-16 are on the same side of the molecule.
• the C-5, C-9, C-13, and C-14 stereocenters of the keto-morphinans are chosen from RRRR, RRRS, RRSR, RRSS, RSRS, RSRR, RSSR, RSSS, SRRR, SRRS, SRSR, SRSS, SSRS, SSRR, SSSR, and SSSS, respectively.
• the C-5, C-9, C-13, and C-14 stereocenters of the keto-morphinans are chosen from RRSR, SRSR, RSRS, and SSRS, respectively.
• the C-5, C-9, C-13, and C-14 stereocenters of the keto- morphinans are RRSR, respectively.
• the C-5, C-9, C-13, and C-14 stereocenters of the keto-morphinans are SSRS, respectively.
• the keto-morphinans are (+)-morphinans. In other aspects of the invention, the keto-morphinans are (-)-morphinans.
• the keto-morphinan is selected from (-)-hydrocodone, (+)-hydrocodone, (-)-naloxone, ⁇ +)- naloxone, (-)-naltrexone, (+)-naltrexone, (-)-naltrexone methyl bromide, (+)-naltrexone methyl bromide, (-)-oxycodone, and (+)-oxycodone.
• the process further comprises contacting the keto-morphinan with a hydroxyamine sulfonic acid.
• a hydroxyamine sulfonic acid comprises both a hydroxyamine group and a sulfonic acid group including various salts thereof. Salts may be any known in the art, including, but not limited to sodium, potassium, and lithium salts.
• the hydroxyamine sulfonic acid comprises the compound HON(S0 3 Na) 2 .
• the hydroxyamine sulfonic acid is hydroxyamine-O-sulfonic acid, H 2 NOSO2OH.
• the keto-morphinan and the hydroxyamine sulfonic acid are combined in a mole-to-mole ratio ranging from about 1 :0.5 to about 1 :10, respectively.
• the keto-morphinan and the hydroxyamine sulfonic acid are combined in a mole-to-mole ratio of about 1 :1 to about 1 :5, respectively.
• the keto-morphinan and the hydroxyamine sulfonic acid are combined in a mole-to-mole ratio ranging from about 1 :1 to about 1 :2, from about 1 :2 to about 1 :3, from about 1 :3 to about 1 :4, or from about 1 :4 to about 1 :5, respectively.
• the keto-morphinan and the hydroxyamine sulfonic acid are combined in a mole-to-mole ratio of about 1 :2, respectively.
• the keto-morphinan and the hydroxyamine sulfonic acid are combined in a mole-to-mole ratio of about 1 :1.5, respectively
• the reaction mixture may further comprise one or more solvents.
• the solvent can and will vary depending on the substrates used in the process.
• the solvent may be a protic solvent, an aprotic solvent, a non-polar solvent, or combinations thereof.
• Suitable examples of protic solvents include, but are not limited to, methanol, ethanol, isopropanol, /7-propanol, isobutanol, n-butanoi, s-butanol, i-butanol, formic acid, acetic acid, water and combinations thereof.
• Non-limiting examples of suitable aprotic solvents include acetonitrile, diethoxymethane, ⁇ , ⁇ -dimethylacetamide (DMAC), N,N- dimethylformamide (DMF), dimethyl sulfoxide (DMSO), N,N-dimethylpropionamide, 1 ,3- dimethyl-3 ,4,5,6-tetrahydro-2(1 H)-pyrimidinone (DMPU), 1 ,3-dimethyl-2-imidazolidinone (DMI), 1 ,2-dimethoxyethane (DME), dimethoxymethane, bis(2-methoxyethyl)ether, 1 ,4- dioxane, N-methyl-2-pyrrolidinone (NMP), ethyl formate, formamide, hexamethylphosphoramide, N-methylacetamide, N-methylformamide, methylene chloride, nitrobenzene, nitromethane, propionitrile, sulfolane,
• non-polar solvents include, but are not limited to, alkane and substituted alkane solvents (including cycloalkanes), aromatic hydrocarbons, esters, ethers, combinations thereof, and the like.
• Specific non-polar solvents that may be employed include, for example, benzene, butyl acetate, t-butyl methylether, chlorobenzene, chloroform, chloromethane, cyclohexane, dichloromethane, dichloroethane, diethyl ether, ethyl acetate, diethylene glycol, fluorobenzene, heptane, hexane, isopropyl acetate, methyltetrahydrofuran, pentyl acetate, n-propyl acetate, tetrahydrofuran, toluene, and combinations thereof.
• the solvents may be present in any ratio without limitation. In one preferred embodiment,
• the weight ratio of the solvent to the keto-morphinan may range from about 0.5:1 to about 100:1. In various embodiments, the weight ratio of the solvent to the keto-morphinan may range from 0.5:1 to about 5:1 , from about 5:1 to about 25:1 , or from about 25:1 to about 100:1. In preferred embodiments, the weight ratio of the solvent to the keto-morphinan may range from about 2:1 to about 10:1.
• the reaction may comprise an additional proton donor.
• the proton donor generally has a p a less than about 6.
• Suitable proton donors having this characteristic include, but are not limited to, acetic acid, formic acid, methane sulfonic acid, phosphoric acid, sulfuric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, trifluoromethane sulfonic acid, toluenesulfonic acid, and the like.
• the molar ratio of the keto-morphinan to the proton donor may range from about 1 :0.5 to about 1 :100. In various embodiments, the molar ratio of the keto-morphinan to the proton donor may range from 1 :10 to about 1 :80, or from about 1 :20 to about 1 :60. In some embodiments, the molar ratio of the keto-morphinan to the proton donor may range be about 1 :1 , or about 1 :5, or about 1 :10, or about 1 :20, or about 1 :30, or about 1 :40, or about 1 :50, or about 1 :60, or about 1 :80, or about 1 :100. In an exemplary embodiment, the molar ratio of the keto-morphinan to the proton donor may be about 1 :40.
• the reaction between the keto-morphinan and the hydroxyamine sulfonic acid may be conducted at a variety of temperatures ranging from about -5°C to about 100°C depending on the substrate and the temperature may vary over the course of the reaction.
• the reaction may be conducted at a about 20°C, or about 25°C, or about 30°C, or about 35°C, or about 40°C, or about 45°C, or about 50°C, or about 55°C, or about 60°C, or about 65°C, or about 70°C, or about 75°C, or about 80°C, or about 85°C, or about 90°C, or about 95°C, or about 100°C, or about 105°C, or about 1 10°C, or about 115°C.
• the reaction may be conducted at a temperature ranging from about 20°C to about Z0 Q C.
• the reaction may be conducted at a temperature of about 25°C.
• reaction completeness may be determined by any method known to one skilled in the art, such as chromatography (e.g., TLC, HPLC, or LC).
• the duration of the reaction may range from about 2 hours to more than 5 days.
• the reaction may be allowed to proceed for about 6 hours, about 12 hours, about 18 hours, about 24 hours, about 36 hours, about 48 hours, about 60 hours, about 72 hours, or about 84 hours.
• a "completed reaction” generally means that the reaction mixture contains a significantly diminished amount of the keto-morphinan.
• the amount of the keto-morphinan remaining in the reaction mixture may be less than about 10%, or more preferably less than about 5%.
• the reaction between the keto- morphinan and the hydroxyamine sulfonic acid reagent results in a sulfonated imine intermediate.
• a sulfonated imine as used herein refers to an imine group N-substituted with a sulfonic acid group.
• the intermediate comprises the compound of Formula (i)(a), below:
• R , R 2 , R 3 , R 5 , R 7 , R 8 , and R 10 are independently chosen from hydrogen, hydrocarbyl, substituted hydrocarbyl, halogen, and ⁇ - ⁇ OR 15 ;
• R 4 is chosen from hydrogen and ⁇ - ⁇ OR 15 ;
• R 15 is chosen from hydrogen, hydrocarbyl, and substituted hydrocarbyl
• R 17 is chosen from hydrogen, hydrocarbyl, and substituted hydrocarbyl.
• the intermediate comprises the compound of Formula (ll)(a), below:
• R , R 2 , R 3 , R 5 , R 7 , R 8 , and R 10 are independently chosen from hydrogen, rocarbyl, substituted hydrocarbyl, halogen, and ⁇ - ⁇ OR 15 ;
• R 14 is chosen from hydrogen and ⁇ - ⁇ OR 15 ;
• R 15 is chosen from hydrogen, hydrocarbyl, and substituted hydrocarbyl;
• R 17 is chosen from hydrogen, hydrocarbyl, substituted hydrocarbyl
• R 18 is chosen from hydrogen, hydrocarbyl, and substituted hydrocarbyl
• X is chosen from fluorine, chlorine, bromine, and iodine.
• the processes may further comprise one or more work-up steps to obtain the seven-membered lactam morphinan.
• the intermediate compound may be converted to the seven-membered lactam morphinan by addition of a proton acceptor.
• the proton acceptor will have a pKa greater than about 9.
• Suitable proton acceptors having this characteristic include ammonia, borate salts (such as, for example, aBOs), bicarbonate salts (such as, for example, NaHC0 3 , KHC0 3) LiC0 3 , and the like), carbonate salts (such as, for example, Na2C0 3 , K 2 C0 3( Li 2 C0 3 , and the like), hydroxide salts (such as, for example, NaOH, KOH, and the like), organic bases (such as, for example, pyridine, methylamine, diethylamine, triethy!amine, diisopropylethylamine, N-methylmorpholine, N,N-dimethyiaminopyridine), and mixtures of any of the above.
• the proton acceptor may be ammonia, ammonium hydroxide, potassium hydroxide, or sodium hydroxide.
• the proton acceptor may be ammonia.
• the proton acceptor may be added in a solvent.
• the solvent can be added before, after, or at the same time as the proton donor.
• the proton acceptor may be present in an aqueous solution.
• the concentration of the proton acceptor in water may vary from about a 1 % v/v solution to about a 99% v/v solution.
• the concentration of the proton acceptor in water may vary from about a 20% v/v solution to about a 60% v/v solution.
• the concentration of the proton acceptor in water may vary from about a 20% v/v solution to about a 30% v/v solution.
• the concentration of the proton acceptor in water is about a 29% v/v solution, in an exemplary embodiment, the proton acceptor may be an aqueous solution of about 29% of ammonia in water.
• the total amount of proton acceptor added to work up the reaction can and will vary. In some embodiments, a proton acceptor is added until the pH of the reaction mixture is above 9. In other embodiments, the proton acceptor is added until the pH of the reaction mixture is about 9, or about 9.2, or about 9.4, or about 9.6.
• the reaction is worked-up through addition of an organic solvent.
• the organic solvent may be added to the reaction in any amount. In some embodiments, the organic solvent is added in excess to the reaction mixture.
• the weight ratio of the keto-rnorphinan to the organic solvent may range from about 1 :10 to about 1 :100. In various embodiments, the weight ratio of the keto- rnorphinan to the organic solvent may range from 1 :1 to about 1 :5, from about 1 :5 about 1 :25, or from about 1 :25 to about 1 :100. In preferred embodiments, the weight ratio of the keto-morphian to the organic solvent is about 1 :50.
• the organic solvent may be selected from those listed in Section (I). In an exemplary embodiment, the organic solvent is acetone.
• work up of the reaction occurs at temperatures ranging from about -10°C to about 50°C.
• the formation of the seven-membered lactam occurs at about -5°C, or at about 0°C, or at about 5°C, or at about 10°C, or at about 20°C, or at about 30°C.
• formation of the seven-membered lactam occurs over 1 hour to about 1 day.
• the yield of the seven-membered lactam morphinan can and will vary. Typically, the yield of the seven-membered lactam morphinan will be at feast about 60%. In one embodiment, the yield of the seven-membered lactam morphinan may range between about 60% and about 80%. In another embodiment, the yield of the seven-membered lactam morphinan may range between about 80% and about 90%. In a further embodiment, the yield of the seven-membered lactam morphinan may range between about 90% and about 95%. In still another embodiment, the yield of the seven-membered lactam morphinan may be greater than about 95%.
• the seven-membered lactam morphinan may be used or it may be converted to another compound using techniques familiar to those of skill in the art.
• the seven-membered lactam morphinan may be converted into a pharmaceutically acceptable salt or may be further chemically derivatized.
• the seven-membered lactams may be produced with a high level of regioselectivity.
• regioselectivity preferential production of a single isomer is called regioselectivity.
• Formation of a lactam from a keto-morphinan as described herein may result in nitrogen insertion at different positions. For example, formation of a lactam from a 6-keto- morphinan may result in nitrogen atom insertion between the 5 position and the carbonyl, or between the 7-position and the carbonyl as shown in Example 1.
• the reaction proceeds with a high level of regioselectivity.
• the reaction produces a single regioisomer in a yield above about 70%, above about 75%, above about 80%, above about 85%, or above about 90%. In yet another embodiment, the reaction produces a single regioisomer in a yield above about 95%.
• the process produces a compound comprising Formula (III) as shown in Reaction Scheme 1.
• Formula (I) Formula (111) wherein R , R 2 , R 3 , R 5 , R 7 , R 8 , and R 10 are independently chosen from hydrogen, hydrocarbyl, substituted hydrocarbyl, halogen, and ⁇ - ⁇ OR 15 ;
• R 14 is chosen from hydrogen and ⁇ - ⁇ OR 15 ;
• R 5 is chosen from hydrogen, hydrocarbyl, and substituted hydrocarbyl
• R 17 is chosen from hydrogen, hydrocarbyl, and substituted hydrocarbyl.
• R , R 2 , R 5 , R 7 , R 8 , and R 10 are hydrogen; R 3 and R 14 are selected from hydrogen, ⁇ - ⁇ OH and ⁇ - ⁇ OCH 3 ; and R 17 is selected from allyl, cyclopropylmethyl, and methyl.
• R 1 , R 2 , R 5 , R 7 , R 8 , R 10 and R 14 are hydrogen; R 3 is ⁇ - ⁇ OCH 3 ; and R 17 is methyl.
• R 1 , R 2 , R 5 , R 7 , R 8 , and R 10 are hydrogen; R 3 is hydroxyl; R 4 is hydroxy!; and R 17 is cyclopropylmethyl.
• R , R 2 , R 5 , R 7 , R 8 , and R 10 are hydrogen; R 3 is hydroxyl; R 4 is hydroxyl; and R 17 is methyl.
• R 1 , R 2 , R 5 , R 7 , R 8 , and R 10 are hydrogen; R 3 is hydroxyl; R 4 is hydroxyl; and R 17 is allyl.
• the process produces a compound comprising Formula (IV) according to Reaction Scheme 2.
• R 1 , R 2 , R 3 , R 5 , R 7 , R 8 , and R 10 are independently chosen from hydrogen, hydrocarbyl, substituted hydrocarbyl, halogen, and ⁇ - ⁇ OR 15 ;
• R 4 is chosen from hydrogen and ⁇ - ⁇ OR 15 ;
• R 15 is chosen from hydrogen, hydrocarbyl, and substituted hydrocarbyl
• R 17 is chosen from hydrogen, hydrocarbyl, and substituted hydrocarbyl
• R 18 is chosen from hydrogen, hydrocarbyl, and substituted hydrocarbyl
• X is chosen from fluorine, chlorine, bromine, and iodine.
• R 1 , R 2 , R 5 , R 7 , R 8 , and R 10 are hydrogen; R 3 is hydroxyl; R 14 is hydroxy!; R 7 is cyciopropylmethyl; R 8 is methyl; and X is bromine.
• the reaction may occur with stereoselectivity.
• the reaction comprises an amount of a single enantiomer greater than about 50%, or greater than about 60%, or greater than about 70%, or greater than about 80%, or greater than about 90%.
• the seven-membered lactam morphinans may have a (-) or a (+) orientation with respect to the rotation of polarized light. More specifically, each chiral center of the morphinan may have an R or an S configuration. In some embodiments, the seven-membered lactam morphinans have at least four chiral centers C-5, C-9, C- 13, and C-14.
• the configurations C-5, C-9, C- 3, and C-14, respectively may be stereocenters of the lactam morphinans are chosen from RRRR, RRRS, RRSR, RRSS, RSRS, RSRR, RSSR, RSSS, SRRR, SRRS, SRSR, SRSS, SSRS, SSRR, SSSR, and SSSS, respectively.
• the C-5, C-9, C-13, and C-14 stereocenters of the seven-membered lactam-morphinans are chosen from RRSR, SRSR, RSRS, and SSRS, respectively.
• the C-5, C-9, C-13, and C-14 stereocenters of the seven-membered lactam morphinans are RRSR, respectively.
• the C-5, C-9, C-13, and C-14 stereocenters of the seven- membered lactam morphinans are SSRS, respectively.
• the keto-morphinans are (+)-morphinans. In other aspects of the invention, the keto-morphinans are (-)-morphinans.
• acyl denotes the moiety formed by removal of the hydroxyl group from the group COOH of an organic carboxylic acid, e.g., C(0)-, wherein R is R , R 1 0-, R 1 R N-, or R S-, R 1 is hydrocarbyl, heterosubstituted hydrocarbyl, or heterocyclo, and R 2 is hydrogen, hydrocarbyl, or substituted hydrocarbyl.
• acyloxy as used herein alone or as part of another group, denotes an acyl group as described above bonded through an oxygen linkage (O), e.g., RC(0)0- wherein R is as defined in connection with the term "acyl.”
• O oxygen linkage
• alkyl as used herein describes groups which are preferably lower alkyl containing from one to eight carbon atoms in the principal chain and up to 20 carbon atoms. They may be straight or branched chain or cyclic and include methyl, ethyl, propyl, isopropyi, butyl, hexyl and the like.
• alkenyl as used herein describes groups which are preferably lower alkenyl containing from two to eight carbon atoms in the principal chain and up to 20 carbon atoms. They may be straight or branched chain or cyclic and include ethenyl, propenyl, isopropenyl, butenyl, isobutenyl, hexenyl, and the like.
• alkoxide or "alkoxy” as used herein is the conjugate base of an alcohol.
• the alcohol may be straight chain, branched, cyclic, and includes aryloxy compounds.
• alkynyl as used herein describes groups which are preferably lower alkynyl containing from two to eight carbon atoms in the principal chain and up to 20 carbon atoms. They may be straight or branched chain and include ethynyl, propynyl, butynyl, isobutynyl, hexynyl, and the like.
• aromatic as used herein alone or as part of another group denotes optionally substituted homo- or heterocyclic conjugated planar ring or ring system comprising delocalized electrons.
• aromatic groups are preferably monocyclic (e.g., furan or benzene), bicyclic, or tricyclic groups containing from 5 to 14 atoms in the ring portion.
• aromatic encompasses "aryl” groups defined below.
• aryl or “Ar” as used herein alone or as part of another group denote optionally substituted homocyclic aromatic groups, preferably monocyclic or bicyclic groups containing from 6 to 10 carbons in the ring portion, such as phenyl, biphenyl, naphthyl, substituted phenyl, substituted biphenyl, or substituted naphthyl.
• enrichment means an amount above the statistical distribution if all chiral centers had an equal probability of being alpha or beta.
• substituents include one or more of the following groups: hydrocarbyl, substituted hydrocarbyl, alkyl, alkoxy, acyl, acyloxy, alkenyl, alkenoxy, aryl, aryloxy, amino, amido, acetal, carbamyl, carbocyclo, cyano, ester, ether, halogen, heterocyclo, hydroxyl, keto, ketal, phospho, nitro, and thio.
• epoxy or "epoxide” as used herein means a cyclic ether.
• the ring structure generally comprises from 2 to 5 carbon atoms in the ring.
• halogen or halo as used herein alone or as part of another group refer to chlorine, bromine, fluorine, and iodine.
• heteroatom refers to atoms other than carbon and hydrogen.
• heteroaromatic as used herein alone or as part of another group denotes optionally substituted aromatic groups having at least one heteroatom in at least one ring, and preferably 5 or 6 atoms in each ring.
• the heteroaromatic group preferably has 1 or 2 oxygen atoms and/or 1 to 4 nitrogen atoms in the ring, and is bonded to the remainder of the molecule through a carbon.
• Exemplary groups include furyl, benzofuryl, oxazolyl, isoxazolyl, oxadiazolyl, benzoxazolyl, benzoxadiazolyl, pyrroiy!, pyrazolyl, imidazolyl, triazoiyl, tetrazoly!, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, indoiyl, isoindolyi, indolizinyl, benzimidazolyl, indazolyl, benzotriazolyl, tetrazolopyridazinyl, carbazolyl, purinyl, quinolinyl, isoquinolinyl, imidazopyridyl, and the like.
• substituents include one or more of the following groups: hydrocarbyl, substituted hydrocarbyl, alkyl, alkoxy, acyl, acyloxy, alkenyl, alkenoxy, aryl, aryloxy, amino, amido, acetal, carbamyi, carbocyc!o, cyano, ester, ether, halogen, heterocyclo, hydroxyl, keto, ketal, phospho, nitro, and thio.
• heterocyclo or “heterocyclic” as used herein alone or as part of another group denote optionally substituted, fully saturated or unsaturated, monocyclic or bicyclic, aromatic or non-aromatic groups having at least one heteroatom in at least one ring, and preferably 5 or 6 atoms in each ring.
• the heterocyclo group preferably has 1 or 2 oxygen atoms and/or 1 to 4 nitrogen atoms in the ring, and is bonded to the remainder of the molecule through a carbon or heteroatom.
• Exemplary heterocyclo groups include heteroaromatics as described above.
• substituents include one or more of the following groups: hydrocarbyl, substituted hydrocarbyl, alkyl, alkoxy, acyl, acyloxy, alkenyl, alkenoxy, aryl, aryloxy, amino, amido, acetal, carbamyi, carbocyclo, cyano, ester, ether, halogen, heterocyclo, hydroxyl, keto, ketal, phospho, nitro, and thio.
• hydrocarbon and “hydrocarbyl” as used herein describe organic compounds or radicals consisting exclusively of the elements carbon and hydrogen. These moieties include alkyl, alkenyl, alkynyl, and aryl moieties. These moieties also include alkyl, alkenyl, alkynyl, and aryl moieties substituted with other aliphatic or cyclic hydrocarbon groups, such as alkaryi, alkenaryl and alkynaryl. Unless otherwise indicated, these moieties preferably comprise 1 to 20 carbon atoms.
• protecting group denotes a group capable of protecting a particular moiety, wherein the protecting group may be removed, subsequent to the reaction for which the protection is employed, without disturbing the remainder of the molecule.
• a variety of protecting groups and the synthesis thereof may be found in "Protective Groups in Organic Synthesis" by T.W. Greene and P.G.M. Wuts, John Wiley & Sons, 1999.
• substituted hydrocarbyl moieties described herein are hydrocarbyl moieties which are substituted with at least one atom other than carbon, including moieties in which a carbon chain atom is substituted with a heteroatom such as nitrogen, oxygen, silicon, phosphorous, boron, or a halogen atom, and moieties in which the carbon chain comprises additional substituents.
• substituents include alkyl, alkoxy, acyl, acyloxy, alkenyl, alkenoxy, aryl, aryloxy, amino, amido, acetal, carbamyl, carbocyclo, cyano, ester, ether, halogen, heterocyclo, hydroxyl, keto, ketal, phospho, nitro, and thio.
• a sulfonated imine as described herein is an imine group with a sulfur comprising group attached.
• the second precipitate was filtered, washed with distilled water (5.0 mL), and then dried on the funnel for 2h. Combing both precipitates, drying the solids at 50°C for 48h under vacuum yielded the product (2.02g, 5.7 mmol, 82% yield).
• (-)-Oxycodone (2.46g, 7.8 mmol) was dissolved in 96% formic acid (10 mL) at room temperature. This mixture was stirred for 15 minutes to ensure complete dissolution. Hydroxyamine O-sulfonic acid (2.21 g, 19.5 mmol, 2.5 eq) was added all at once. The reaction stirred for 72h at room temperature where the reaction was deemed complete by LC. To the solution was added distilled water (50 mL) then the solution was cooled between 0°C and 5°C. The pH was adjusted to 9.4 using 29%NHs/ H 2 O added dropwise. A precipitate formed.
• the precipitate was filtered, washed with acetone (25 mL), and dried on the funnel for 1 h. The solid was transferred to a drying dish and dried at 50°C for 48h under vacuum yielded the product (0,86g, 1.8 mmol, 76% yield).
• (+)-Naloxone (0.46g, 1.41 mmoi) was dissolved in 96% formic acid (4.0 mL) at room temperature. This mixture was stirred for 15 minutes to ensure complete dissolution. Hydroxyamine O-sulfonic acid (0.278g, 2.46 mmol, 1.75 eq) was added all at once. The reaction stirred for 24h at room temperature where the reaction was deemed complete by LC. The reaction mixture was added dropwise into a cold solution of 29% NH 3 / H 2 0. A precipitate formed and stirred for 3h at 5°C. The precipitate was isolated by filtration, washed with distilled water (2 x 25 mL), and then dried on the funnel.
• (+)-Oxycodone (1.88g, 7.8 mmol) was dissolved in 96% formic acid (10 mL) at room temperature. This mixture was stirred for 15 minutes to ensure complete dissolution. Hydroxyamine O-sulfonic acid (1.34g, 11.9 mmol, 2.0 eq) was added all at once. The reaction stirred for 24h at room temperature where the reaction was deemed complete by LC. To the solution was added distilled water (50 mL) then the solution was cooled to 25°C. The pH was adjusted to 9.2 using 29%NHs/ H 2 0 added dropwise. A gummy precipitate formed. The solution was extracted using CHCI3 (2 x 50 mL).
• Extracts were combined, dried over anhydrous MgS0 4 ( ⁇ 2.0g), filtered, and evaporated.
• the product was isolated by gravity Si0 2 chromatography (G60, 70-230 mesh) eluting with a gradient from 0% MeOH/ CHC to 5% MeOH/ CHCI 3 .
• Combination of the desired fractions, evaporation, then drying in a vacuum oven at 40°C for 48h yielded the product (1.67 mg, 5.1 mmol, 85% yield) as an off-white foam.
• (+)-Naltrexone (1.53g, 4.48 mmol) was dissolved in 96% formic acid (10 mL) at room temperature. This mixture was stirred for 15 minutes to ensure complete dissolution. Hydroxyamine O-sulfonic acid (1.01g, 8.96 mmol, 2.0 eq) was added all at once. The reaction stirred for 48h at room temperature where the reaction was deemed complete by LC. To the solution was added distilled water (50 mL) then the solution was cooled to 25°C. The pH was adjusted to 9.2 using 29%NH3/ H 2 O added dropwise. A gummy precipitate formed. The solution was extracted using CHCI 3 (3 x 50 mL).
• Extracts were combined, dried over anhydrous MgSO 4 ( ⁇ 2.0g), filtered, and evaporated.
• the product was isolated by gravity S1O2 chromatography (G60, 70-230 mesh) eluting with a gradient from 0% MeOH/ CHCI 3 to 3% MeOH/CHCI 3 .
• Combination of the desired fractions, evaporation, then drying in a vacuum oven at 40°C for 48h yielded the product (1.42g, 4.0 mmol, 89% yield) as an off-white foam.

Landscapes

• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Saccharide Compounds (AREA)

Priority Applications (9)

Applications Claiming Priority (2)

Publications (1)

Family

ID=47430091

Family Applications (1)

Country Status (11)

Families Citing this family (2)

• 2012
  • 2012-12-05 CA CA2856727A patent/CA2856727A1/en not_active Abandoned
  • 2012-12-05 EP EP12806257.7A patent/EP2788360A1/en not_active Withdrawn
  • 2012-12-05 AU AU2012348029A patent/AU2012348029A1/en not_active Abandoned
  • 2012-12-05 MX MX2014006268A patent/MX2014006268A/es not_active Application Discontinuation
  • 2012-12-05 WO PCT/US2012/067821 patent/WO2013085937A1/en active Application Filing
  • 2012-12-05 BR BR112014013515A patent/BR112014013515A2/pt not_active Application Discontinuation
  • 2012-12-05 US US13/705,205 patent/US20130144053A1/en not_active Abandoned
  • 2012-12-05 RU RU2014127179A patent/RU2014127179A/ru unknown
  • 2012-12-05 CN CN201280066231.1A patent/CN104039795A/zh active Pending
  • 2012-12-05 JP JP2014544997A patent/JP2015500245A/ja not_active Withdrawn
  • 2012-12-05 KR KR1020147018044A patent/KR20140099525A/ko not_active Application Discontinuation

Non-Patent Citations (6)

Also Published As

Similar Documents

Legal Events